Curcuminoids and metabolites thereof for treating allergic nasal conditions

ABSTRACT

A pharmaceutical composition for nasal administration comprising: a nanoemulsified curcumin component; a liquid medium for the curcumin component; and a pharmaceutically acceptable excipient. The curcumin component is a natural curcuminoid, a synthetic curcuminoid, a metabolite of a natural or synthetic curcuminoid, or a mixture thereof. The excipient is effective in increasing the bioavailability of the curcumin component.

RELATED APPLICATIONS

The present application is a Continuation of U.S. patent applicationSer. No. 13/241,519, filed Sep. 23, 2011; which is a Continuation ofInternational Application Number PCT/IN2010/000166, entitled“Curcuminoids and Its Metabolites for the Application in AllergicOcular/Nasal Conditions,” filed on Mar. 22, 2010 and now published as WO2010/109482. International Application Number PCT/IN2010/000166 and U.S.patent application Ser. No. 13/241,519 are incorporated by reference intheir entirety.

TECHNICAL FIELD

The present disclosure relates to a therapeutic aqueous nasalcomposition for nasal administration comprising an emulsion of naturalor synthetic curcuminoids and/or their metabolites. The compositions areuseful for the prevention or treatment of allergic nasal conditions andtheir associated symptoms in humans and animals.

BACKGROUND

The eye is a complex and sensitive organ of the body, which canexperience numerous diseases. The eye poses many barriers to protect anydamage to its tissues. This also means that the anterior portion of theeye is more susceptible to diseases. The first and foremost barrier isthe conjunctiva, which is the mucous membrane surrounding the eye ball.It is constantly exposed to many harsh conditions/allergens through theenvironmental factors it encounters. This leads to the allergicreactions in the eye mediated by mast cells through the release ofhistamine leading to the condition called allergic conjunctivitis orother associated inflammatory conditions like redness and swelling ofthe eye. These allergic conditions are either seasonal which occurs onlyduring specific time of the year and is termed seasonal allergicconjunctivitis (SAC) or perennial that occurs throughout the year andtermed perennial allergic conjunctivitis (PAC). Some allergic conditionsextend even to the cornea such as atopic keratoconjunctivitis, vernalconjunctivitis and giant papillary conjunctivitis.

These conditions are typically characterized by red, itchy and swolleneyes with watery discharge. This is largely attributed to thedegranulation of mast cells due to the cross-linking of IgE uponallergen sensitization leading to an outburst of histamine in theconjunctiva. The conjunctiva being rich in mast cells, experiences anoverdose of histamine upon allergen sensitization, resulting in theitching and redness of the eye. Current treatment methods involveanti-histamine drops (emedastine difumarate and levocabastine), topicalmast cell stabilizers (olopatadine, ketotifen), decongestants andtopical anti-inflammatory drugs (NSAID's and corticosteroids).

Allergic rhinitis is an inflammation of the nasal passages, usuallyassociated with watery nasal discharge and itching of the nose and eyes.The symptoms occur in the nose and eyes and usually occur after exposureto dust, danders, or certain seasonal pollens. Patients can be severelyrestricted in their daily activities, resulting in excessive time awayfrom school or work. Millions of dollars are spent each year onphysician services and medication for treatment of this chronic illness.Many perennial and seasonal allergens cause allergic rhinitis the formergiving rise to perennial allergic rhinitis (PAR) and the latter givingrise to seasonal allergic conjunctivitis (SAR).

Dust mites, cockroaches, molds and animal dander, are examples ofyear-around allergens.

Characteristic symptoms include repetitive sneezing; rhinorrhea (runnynose); post-nasal drip; nasal congestion; pruritic (itchy) eyes, ears,nose or throat; and generalized fatigue. Symptoms can also includewheezing, eye tearing, sore throat, and impaired smell. A chronic coughmay be secondary to postnasal drip, but should not be mistaken forasthma. Sinus headaches and ear plugging are also common.

Anti-Histamines and Decongestants for Allergic Conjunctivitis

Anti-histamines are available for treating Allergic Conjunctivitis andare available in the market as tablets, capsules and liquids, and may ormay not be combined with decongestants. Common anti-histamines includebrompheniramine or chlorpheniramine, and clemastine. Non-sedating (lesslikely to cause drowsiness) long-acting anti-histamines includeloratidine and fexofenadine. Oral decongestants alone may be helpful,including pseudoephedrine.

Nasal Sprays

For rhinorrhea, a nasal spray of cromolyn sodium (Nasalcrom) or asteroid nasal spray, such as flunisolide (Nasalide), beclomethasonedipropionate (Beconase, Vancenase), triamcinolone acetonide (Nasacort),and fluticasone (Flonase), may work so well that additionalanti-histamines or decongestants are unnecessary. It is important toremember that improvement may not occur for one to two weeks afterstarting therapy with steroid nasal sprays. Short courses of oralcorticosteroids may usually be indicated when severe nasal symptomsprevent the adequate delivery of topical agents. But due to theirunpleasant side-effects, there has been a tremendous surge in demand fornon-steroidal, plant based anti-inflammatory and anti-allergic agentsand their potential use in various therapeutic applications.Curcuminoids are one such class of compounds that have provenanti-inflammatory and anti-allergic properties.

Curcuminoids are natural, polyphenolic compounds present in turmeric inthree different forms a) Curcumin b) Bisdemethoxy curcumin and c)Demethoxy curcumin. Curcumin is the principal curcuminoid and hasexceptionally potent antioxidant and anti-inflammatory activity, whichcan prevent cell damage caused by free-radicals (oxidative stress) andinflammation. The current level of interest on curcumin and itsanalogs/derivatives is known from the below mentioned articles.

Process for producing enriched fractions of bis-o-demethylcurcumin andtetrahydrotetrahydroxy-curcumin from the extracts of curcuma longa isdisclosed in our earlier PCT Application #WO/2007/043058. According tothis publication, bis-o-demethyl curcumin shows most potent anticancer,anti-oxidative and anti-inflammatory activity when compared to othercurcuminoids and the natural mixture of curcumins.

However, the use of natural curcuminoids, such as curcumin,bisdemethoxycurcumin demethoxycurcumin and synthetically derivedbis-o-demethyl curcumin and/or other demethylated curcuminoids eitheralone or in combination in ophthalmic formulations is not known in theprior art. Natural curcuminoids, such as curcumin, bisdemethoxycurcumindemethoxycurcumin and synthetically derived bis-o-demethyl curcuminand/or other demethylated curcuminoids either alone or in combinationbeing a lipophilic drug have low aqueous solubility, and hence restrictthe therapeutic availability of the same.

All curcuminoids, both natural and synthetic have lipophilic structureswith conjugated double bonds with a keto group thus rendering them tohave a dielectric constant which will interact with negatively chargedmembranes making it unable to permeate through the biological membrane.Thus, for these curcuminoids to pass through membranes, it is necessaryto encapsulate these molecules with lipophilic molecules. Moreover, itis necessary to make the lattice of molecules as a single entity so thatthese encapsulated molecules can be transported across membranes.

Anti-allergic and anti-inflammatory drugs are classified intoanalgesics, anti-histamines, anti-microbials, corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). These classes of drugs areused to treat variety of ocular disorders. Prolonged use ofcorticosteroids, NSAIDs, and the other groups of above mentioned classesof drugs results in glaucoma, optic nerve damage, vision problems,cataract, or secondary ocular infections.

Accordingly, the current disclosure provides a potential successor inthe field of ophthalmology with a novel phytopharmaceutical compositionfor the treatment of ocular and nasal diseases/disorders. Surprisingly,preliminary experiments conducted have demonstrated the use ofsurfactants and cosolvents in solubilizing curcuminoids up to 200 mg w/vthereby aiding effective solubilization in aqueous medium. The currentmethod involves coating of curcuminoids using surfactants and acosolvent in order to enhance the curcuminoids aqueous solubility andhence its permeation across the cell membrane.

Therefore, the current disclosure describes hitherto unexploited andnovel ophthalmic composition(s) comprising natural curcuminoids, such ascurcumin, bisdemethoxycurcumin demethoxycurcumin and syntheticallyderived bis-o-demethyl curcumin and/or other demethylated curcuminoidseither alone or in combination, together with surfactants and/orcosolvents as aqueous ophthalmic composition(s) in the form ofgel/suspension/ointment for ocular diseases or disorders.

SUMMARY

In a first aspect, the disclosure describes a formulation for nasaladministration comprising a liquid medium and natural or syntheticcurcuminoids and/or their metabolites. The curcuminoids or metabolitesthereof may be curcumin, bisdemethoxycurcumin, demethoxycurcumin, orsynthetically derived bis-O-demethyl curcumin and/or other demethylatedcurcuminoids. The curcuminoids may be present in the formulation aloneor optionally in combination with a surfactant and/or a cosolvent, alongwith suitable ophthalmic excipients for inflammatory diseases of the eyesuch as allergic conjunctivitis. The curcuminoids may be nano-emulsifiedin the liquid medium, which serves as a carrier for the curcuminoids.

In another aspect, the disclosure describes a nasal spray comprisingnatural curcuminoids and/or its metabolites, such as curcumin,bisdemethoxycurcumin, demethoxycurcumin and/or synthetically derivedbis-o-demethyl curcumin and/or other demethylated curcuminoids eitheralone or in combination with nonionic surfactant, cosolvent along withsuitable excipients for inflammatory diseases of nose such as allergicrhinitis.

In another aspect, the disclosure describes formulation for nasalapplication enclosed herewith is a spray comprising curcumin,bisdemethoxycurcumin, demethoxycurcumin and/or synthetically derivedbis-o-demethyl curcumin and/or other demethylated curcuminoids eitheralone or in combination with pharmaceutically acceptable excipients orsuitable nasal excipients.

In another aspect, the disclosure describes compositions comprising oneor more Curcuma derived components obtained naturally or by synthesis orsemi-synthesis for preparing compositions described in the presentdisclosure.

In another aspect, the method of administration of natural curcuminoidsand/or its metabolites, like curcumin, bisdemethoxycurcumin,demethoxycurcumin and/or synthetically derived bis-o-demethyl curcuminand other demethylated curcuminoids either alone or optionally incombination with a pharmaceutically acceptable excipients or carriers ordiluents in a therapeutically effective amount to prevent, retard thedevelopment or to reduce the symptoms of several inflammatory diseasessuch as allergic conditions of the nasal tract.

In another aspect the disclosure describes use of the disclosedcompositions for prevention and treatment of nasal allergic conditionsin animals and humans.

In yet another aspect the disclosure describes methods for treating orpreventing nasal allergic conditions in animals and humans, wherein saidmethod comprises administration of therapeutically effective amount ofthe disclosed compositions.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: FIG. 1 depicts a comparison of intracellular transport ofnanoemulsified curcumin with plain curcumin and the confocal pictures ofnano emulsified curcuminoids and non-nano emulsified curcuminoids at 5minutes, 10 minutes and 25 minutes.

FIG. 2: FIG. 2 depicts a comparison of intestinal uptake ofnanoemulsified curcumin with plain curcumin and the confocal pictures ofnano emulsified curcumin and non-nano emulsified curcumin at 1 hour timeintervals in two different animal groups.

FIG. 3: FIG. 3 depicts a Particle Size Study using a Malvern particlesize analyzer.

FIG. 4: FIG. 4 depicts a TEM Micrograph: “Morphology of nano-emulsionunder TEM.”

FIG. 5: FIG. 5 depicts a SEM Micrograph: “Morphology of nano-emulsionunder SEM.”

FIG. 6: FIG. 6 depicts a FRAP assay showing total anti-oxidant activityof curcumin.

FIG. 7: FIG. 7 depicts a line diagram showing inhibition ofβ-hexosaminidase release from PMA-induced U937 human monocytesconcomitantly treated with different concentrations curcumin (formulatedand non-formulated) as indicated. β-hexosaminidase released form theuntreated control cells are considered as 100%. Results represented asthe mean from quadruplicate culture wells.

FIG. 8: FIG. 8 depicts line diagram showing inhibition of histaminerelease from PMA-induced U937 human monocytes concomitantly treated withdifferent concentrations of nonformulated and formulated curcumin.

DETAILED DESCRIPTION

Various embodiments are now described, so that various aspects thereofmay be more fully understood and appreciated.

As used herein the term ‘curcuminoid’ or ‘curcuminoids’ means one ormore curcuma derived components comprising natural curcuminoids, such ascurcumin, bisdemethoxycurcumin, demethoxycurcumin and/or syntheticallyderived bis-o-demethyl curcumin and/or other demethylated curcuminoidseither alone or optionally in combination with one or morepharmaceutically acceptable excipients for several inflammatory andallergic diseases in humans and animals in need thereof.

As used herein the term ‘surfactant’ or ‘surfactants’ means surfaceactive agent(s) which works by lowering the surface tension of water andenabling solubility of lipophilic compounds.

The surfactants in nature are amphiphilic, meaning they contain ahydrophobic tail and a hydrophilic head. Therefore, these are soluble inboth hydrophobic medium and water. The surfactants are of 2 types a)ionic (anionic and cationic) b) nonionic. The current disclosuredescribes the use of anionic, cationic and/or nonionic surfactants forpharmaceutical purposes. The surfactants used in the current disclosurecan be selected from but not limited to polysorbate 80 and 20,poloxamers, octoxynol and any other pharmaceutically acceptablesurfactant(s) suitable for preparing the compositions of the presentdisclosure.

Accordingly, in one embodiment, the current disclosure provides anaqueous ophthalmic (topical) eye drop or ophthalmic gel formulationcomprising one or more Curcuma derived component(s) and theirmetabolites preferably selected from natural curcuminoids, such ascurcumin, bisdemethoxycurcumin, demethoxycurcumin and/or syntheticallyderived bis-o-demethyl curcumin and/or other demethylated curcuminoidseither alone or optionally in combination with pharmaceuticallyacceptable surfactant(s), cosolvent or suitable ophthalmic excipient(s).

In another embodiment, the disclosure provides a nasal spray comprisingone or more Curcuma derived component(s) and their metabolitespreferably selected from natural curcuminoids, such as curcumin,bisdemethoxycurcumin, demethoxycurcumin and/or synthetically derivedbis-o-demethyl curcumin and/or other demethylated curcuminoids eitheralone or in combination along with suitable excipient(s).

In yet another embodiment, the present disclosure provides an aqueousophthalmic (topical) eye drop or ophthalmic gel formulation comprisingan effective amount of natural/synthetic curcuminoids and an amount ofpharmaceutically acceptable surfactant(s) and a cosolvent or suitableophthalmic excipient(s) effective in increasing the bioavailability ofthe lipophilic curcuminoids, when administered topically to the eye oran ointment comprising an effective amount of natural/syntheticcurcuminoids administered topically to the eye to effectively treatseveral inflammatory and allergic conditions of the eye and nasal tract.

The present disclosure also provides an ophthalmic eye drop dispensercontaining an ophthalmic (topical) composition comprising an effectiveamount of natural/synthetic curcuminoids, and a pharmaceuticallyacceptable surfactant(s) and a cosolvent in a therapeutically effectiveamount to effectively increase the solubility of the naturally active orsynthetic component(s) used for preparing the composition(s). Thecomposition(s) of this disclosure are devoid of any side effects andalso effective in prolonging the therapeutic effect of the active agent,when administered to the eye.

The present disclosure also provides a nasal spray container comprisinga nasal spray composition of an effective amount of one or morenatural/synthetic curcuminoids, and in combination with an amount ofpharmaceutically acceptable agent(s) such as nonionic surfactant(s) anda cosolvent(s) or suitable nasal excipient(s) effectively to increasethe solubility of the naturally active or synthetic component(s) usedfor preparing the composition(s).

The disclosure describes pharmaceutical drug(s) derived from one or moreCurcuma component(s) obtained either naturally or by synthetic or bysemi-synthesis. Curcuma or Turmeric is a commonly used spice andcoloring agent used in India, and is available from wide sources, havingpotent antiinflammatory, anti-oxidant and anti-allergic action with noside effect.

Curcumin was reported to have anti-allergic properties with inhibitoryeffect on histamine release from mast cells. The effectiveness ofcurcumin in allergy and asthma has been further investigated using amurine model of allergy. The results indicate a marked inhibition ofallergic response in animals treated with curcumin suggesting a majorrole for curcumin in reducing the allergic response. The present reviewfocuses on the results of research aimed to understand theimmunomodulation induced by curcumin and its associated roles in theamelioration of allergy. These findings needed further evaluation,extrapolation, and confirmation before using curcumin for controllingallergy and asthma in humans. Kurup et al., “Immunomodulatory effects ofcurcumin in allergy” Mol Nutr Food Res. 2008 September; 52(9):1031-9

The desirable preventive or putative therapeutic properties of curcuminhave also been considered to be associated with its antioxidant andanti-inflammatory properties. Free radical-mediated peroxidation ofmembrane lipids and oxidative damage of DNA and proteins are believed tobe associated with a variety of chronic pathological complications suchas cancer, atherosclerosis, and neurodegenerative diseases. Curcumin isthought to play a vital role against these pathological conditions. Theanti-inflammatory effect of curcumin is most likely mediated through itsability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), andinducible nitric oxide synthase (iNOS). COX-2, LOX, and iNOS areimportant enzymes that mediate inflammatory processes. Improperupregulation of COX-2 and/or iNOS has been associated with thepathophysiology of certain types of human cancer as well as inflammatorydisorders. Because inflammation is closely linked to tumor promotion,curcumin with its potent anti-inflammatory property is anticipated toexert chemopreventive effects on carcinogenesis. Hence, the past fewdecades have witnessed intense research devoted to the antioxidant andanti-inflammatory properties of curcumin. In this review, bothantioxidant and anti-inflammatory properties of curcumin, the mode ofaction of curcumin, and its therapeutic usage against differentpathological conditions are clearly described. Menon V P et al.,Antioxidant and anti-inflammatory properties of curcumin Adv Exp MedBiol. 2007; 595:105-25

Anti-asthmatic property of curcumin (diferuloylmethane), a naturalproduct from the rhizomes of Curcuma longa, has been tested in a guineapig model of airway hyperresponsiveness. The guinea pigs were sensitizedwith ovalbumin (OVA) to develop certain characteristic features ofasthma: allergen induced airway constriction and airway hyper reactivityto histamine. Guinea pigs were treated with curcumin duringsensitization (to examine its preventive effect) or after developingimpaired airways features (to examine its therapeutic effect). Status ofairway constriction and airway hyper reactivity were determined bymeasuring specific airway conductance (SGaw) using a non-invasivetechnique, constant-volume body plethysmography. Curcumin (20 mg/kg bodyweight) treatment significantly inhibits OVA-induced airway constriction(p<0.0399) and airway hyper reactivity (p<0.0043). The resultsdemonstrate that curcumin is effective in improving the impaired airwaysfeatures in the OVA-sensitized guinea pigs. Arjun Ram et al., CurcuminAttenuates Allergen-Induced Airway Hyperresponsiveness in SensitizedGuinea Pigs, Biological & Pharmaceutical Bulletin Vol. 26 (2003), No. 71021.

Thus keeping in mind the above cited references and many otherreferences, in the present disclosure it was aimed to the study undertrial and to test the benefits of the formulation of curcumin in thetreatment or prevention of several inflammatory diseases of eye and nosesuch as Allergic Conjunctivitis/Allergic Rhinitis which is characterizedprimarily by itching, redness and edema of the eye due to histaminerelease.

Accordingly, the present disclosure provides ophthalmiccompositions/formulation in any suitable form, more specifically asophthalmic drops or ophthalmic gel, where the formulation may compriseone or more Curcuma derived components such as curcuminoids availablefrom natural or obtained by synthesis or semi-synthesis.

In a preferred embodiment, the active agents that may be used include,but are not limited to, constituents of natural curcumin mixturecomprising natural curcuminoids, such as curcumin, bisdemethoxycurcumin,demethoxycurcumin and/or synthetically derived bis-o-demethyl curcuminand/or other demethylated curcuminoids either alone or in combinationhaving antioxidant or anti-inflammatory activity. The concentration oftotal curcuminoids in the compositions of the present disclosure mayvary from 0.01% to 5.0% w/v; preferably between 0.05% and 2.5%; morepreferably between about 0.05% to about 0.15% w/v, with an effectiveconcentration of 0.06%. The curcumin components can be derived from oneor more curcuma species comprising Curcuma longa, Curcuma aromatica andCurcuma Zedoaria.

According to the disclosure the drug and surfactants can be combinedwith acceptable carriers to formulate a stable ophthalmic preparationwith enhanced bioavailability and stability. These carriers includepharmaceutically acceptable excipients and additives selected from butnot limited to water soluble polymers, chelating agents, stabilizingagents, isotonizing agents, buffer substances, preservatives,thickeners, complexing agents, electrolytes and other excipients.

The water soluble polymers are selected from but not limited tomethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, sodiumcarboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,polyethylene glycol, poly(methyl methacrylate), polycarbophil, gelatin,alginate, poly(acrylic acid), polyethylene oxide and chitosan or aderivative thereof.

The surfactant(s) can be anionic, cationic or non-ionic, selected frombut not limited to polysorbate 80 and 20, polyethylene glycol esters,polyethylene glycols, glycerol ethers or mixtures of those compounds.

The co-solvents are selected from but not limited to monohydric alcoholor polyhydric alcohols such as polyethylene glycol, polypropyleneglycoland the like.

The composition further comprises a chelating agent such as disodiumsalt of EDTA. The composition may comprise suitable water solublepolymers which may be used in the disclosed compositions, including, butnot limited to methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose,sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,polyethylene glycol, poly(methyl methacrylate), polycarbophil, gelatin,alginate, poly(acrylic acid), polyethylene oxide and chitosan or aderivative thereof.

The stabilizing agent in the present composition comprises of but is notlimited to sodium hydrogen sulfite, glycerin, sodium citrate, butylhydroxyanisole, benzalkonium chloride, edetic acid and pharmaceuticallyacceptable salts thereof, tocopherol and derivatives thereof, optionallyin combination with sodium edetate.

The isotonizing agent used in the composition comprises of but is notlimited to any specific one like sodium chloride, potassium chloride,D-mannitol, glucose, glycerin, xylitol and propylene.

In various embodiments, the thickening agent is methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone,polyvinyl alcohol, sodium chondroitin sulfate, sodium hyaluronate orchitosan; however, the thickening agent is not limited to thesepolymers. Thickening agents are used to maintain the viscosity of theliquid formulations. Accordingly, the pharmaceutical composition(s) fornasal administration of the present disclosure comprise one or morenanoemulsified curcumin component or a metabolite thereof, selected fromnatural or synthetic curcuminoid(s). The compositions have a viscosityin the range of 5-20 centipoises.

The preservatives which may be used include but not limited to, sodiumbisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuricnitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol.

The buffering agents that may be used include, but are not limited to,sodium carbonate, sodium tetraborate, sodium phosphate, sodium acetate,sodium bicarbonate.

Electrolytes such as sodium chloride and potassium chloride may also beincluded in the formulation.

The ophthalmic/intra-nasal aqueous pharmaceutical preparation of thepresent disclosure may be charged in an appropriate container for betterdrug delivery.

The dosage form of the ophthalmic aqueous pharmaceutical preparation ofthe present disclosure is not limited to an eye drop, but may beprepared as ophthalmic gel. For instance, the ophthalmic aqueouspharmaceutical suspension preparation of the present disclosure canwidely be used for the treatment of all the anterior and posteriorrelated conditions or ocular diseases.

The dosage form of the intra-nasal aqueous pharmaceutical preparation ofthe present disclosure is not limited to nasal spray and can be preparedas nasal drops also.

Furthermore, the ophthalmic/nasal aqueous solution preparation of thepresent disclosure comprises a non-steroidal drug. Therefore, it may bedevoid of any side effect even if it is administered for a prolongedperiod of time with a low probability of damaging corneal/nasalepithelial cells or the conjunctival cells.

Potent curcuminoids such as curcumin, bis-o-demethyl curcumin suppressinflammation by inhibiting edema, fibrin deposition, capillary leakageand phagocytic migration, all key features of the inflammatory response.These curcuminoids prevent the release of prostaglandins, some of whichhave been identified as mediators of cystoid macular edema.Additionally, curcuminoids including bis-o-demethyl curcumin have beenshown to inhibit the expression of vascular endothelial growth factor(VEGF), a cytokine which is a potent promoter of vascular permeability.

In order to further validate the hypothesis of the anti-allergicactivity of curcuminoids certain ex-vivo and in vivo studies can beperformed. Guinea pig ileum study would be an ideal ex-vivo experimentwhere the allergen sensitized guinea pig ileum is treated with theformulation and assessed for its efficacy. In the same way theformulation can be tested in vivo by sensitizing the animals withhistamine and treating with the formulation and assessing for itsefficacy.

The use of curcuminoids to date, by conventional routes ofadministration, has yielded limited success in treating eye disorders,including macular edema, largely due to the inability to deliver andmaintain adequate quantities of the drug to the posterior segmentwithout resultant toxicity. For example, after usual topicaladministration of ophthalmic drops, only about 1% reaches the anteriorsegment, and only a fraction of that amount moves into the posteriorsegment. Although intravitreal injections of drug have been used, theexposure to the drug is very brief as the half-life of the drug withinthe eye is approximately 3 hours.

In our previous Indian patent application #PCT/IN2009/000651, a processof solubilization of natural or synthetic curcumin and othercurcuminoids has been described using surfactants and cosolvents withthe help of sonar energy.

It was also found that the nanoemulsified curcumin was effectively takenup by the cells when compared to the normal curcumin. The nanoemulsifiedcurcumin increases the pharmacokinetics and pharmacodynamics propertiesthereby having a better therapeutic effect. This process enhances theuptake of curcumin and thereby having a potent therapeutic effect. Thenanoemulsification process enhances the anti-allergic activity ofcurcumin thus increasing the effectiveness of the formulation whencompared with any other known therapeutic agents.

The nanoparticle size of curcumin in the present disclosure was found tobe between 10-20 nm in size. However, the nanodroplet size can vary from5-500 nm, preferably 5-100 nm and more preferably 5-30 nm. Transmissionelectron microscope (TEM) and Scanning electron microscope (SEM) studieswere conducted on the nanoemulsion to confirm the shape and size of thenano particles.

A typical eye drop/nasal spray formulation(s) of the present disclosurecomprises of one or more Curcumin derived components selected from anaqueous drug suspension of solid natural curcuminoids, such as curcumin,bisdemethoxycurcumin demethoxycurcumin and synthetically derivedbis-o-demethyl curcumin and/or other demethylated curcuminoids withantioxidant or anti-inflammatory activity optionally in combination withpharmaceutically acceptable excipient(s) selected from but not limitedto nonionic surfactant preferably cyclodextrin complexes, water-solublepolymers such as hydroxypropyl methylcellulose, and other cellulosederivatives, chelating agent, metal ions (such as magnesium ions) and/ororganic salts such as sodium acetate and sodium citrate, where suchadditives are used to stabilize the system with enhanced mucoadhesiveproperties.

In yet another embodiment, the disclosure describes use of the disclosedcompositions for prevention and treatment of ocular and nasal allergicconditions in animals and humans.

Use of the compositions disclosed herein is applicable for preventionand treatment of conditions associated with eye such as allergicconjunctivitis, atopic keratoconjunctivitis, vernal conjunctivitis,giant papillary conjunctivitis and conditions thereof.

Use of the compositions disclosed herein is applicable for treatment andprevention of conditions associated with nose such as allergic rhinitis.The disclosure further provides the use of the recited compositions isapplicable for treatment and prevention of asthma.

In another embodiment, the method of administration of naturalcurcuminoids and/or its metabolites, like curcumin,bisdemethoxycurcumin, demethoxycurcumin and/or synthetically derivedbis-o-demethyl curcumin and other demethylated curcuminoids either aloneor optionally in combination with a pharmaceutically acceptableexcipients or carriers or diluents in a therapeutically effective amountto prevent, retard the development or to reduce the symptoms of severalinflammatory diseases such as allergic conditions of the eye/conjunctivaand/or the nasal tract.

In another embodiment, the disclosure describes methods of reducing orpreventing or retarding the development of conditions associated withthe eye such as allergic conjunctivitis, atopic keratoconjunctivitis,vernal conjunctivitis, giant papillary conjunctivitis which compriseadministering an effective amount of the disclosed compositions to asubject suffering with said conditions.

In another embodiment, the disclosure describes a method of treating andpreventing Asthma comprises administering an effective amount of thedisclosed composition to a subject suffering with asthma.

In yet another embodiment, the disclosure describes a method of treatingand preventing conditions associated with the nose such as allergicrhinitis, which comprises administering an effective amount of thedisclosed composition to a subject suffering with said conditions.

The subject mentioned in the above methods is animal or humans.

Having described various embodiments, other embodiments will becomeapparent to one skilled in the art from consideration of thespecification. The invention is further described by reference to thefollowing non-limiting examples. It will be apparent to those skilled inthe art that any modifications, both to materials and methods, may bepracticed without departing from the scope of the invention.

EXAMPLES Example 1 Preparation of Formulation-1

TABLE 1 S. No Ingredients Concentration 1 Natural/synthetic 20-2500 mgcurcuminoid 2 Polyethylene Glycol 0.7 g-1 g 4 Tween 80 0.7 g-1 g 6Hydroxy Propyl Methyl 0.1 g Cellulose 7 Benzalkonium Chloride 20 mg 8Ethylene Diamine Tetra 100 mg Acetic Acid (disodium salt) 9 Sodiumtetraborate (0.1 M) 3.81 g 10 Boric acid (1 M) 6.8 g 11 NaCl 0.795 g 12Sterile water for Injection 100 ml

Example 2 Preparation of Formulation-2

TABLE 2 S. No Ingredients Concentration 1 Natural/synthetic 20-2500 mgCurcuminoid 2 Polyethylene Glycol 0.7 g-1 g 4 Tween 20 0.7 g-1 g 6Hydroxy Propyl Methyl 0.1 g Cellulose 7 Benzalkonium Chloride 20 mg 8Ethylene Diamine Tetra 100 mg Acetic Acid (disodium salt) 9 Sodiumtetraborate (0.1 M) 3.81 g 10 Boric acid (1 M) 6.8 g 11 NaCl 0.795 g 12Sterile water for Injection 100 ml

Example 3 Preparation of Formulation-3

TABLE 3 S. No Ingredients Concentration 1 Natural/synthetic 20-2500 mgCurcuminoid 2 Polyethylene Glycol 0.7 g-1 g 4 Octoxynol 0.7 g-1 g 6Hydroxy Propyl Methyl 0.1 g Cellulose 7 Benzalkonium Chloride 20 mg 8Ethylene Diamine Tetra 100 mg Acetic Acid (disodium salt) 9 Sodiumtetraborate (0.1 M) 3.81 g 10 Boric acid (1 M) 6.8 g 11 NaCl 0.795 g 12Sterile water for Injection 100 ml

Example 4 Preparation of Formulation-4

TABLE 4 S. No Ingredients Concentration 1 Natural/synthetic 20-2500 mgCurcumin 2 Polyethylene Glycol 0.7 g-1 g 4 Poloxamers 0.7 g-1 g 6Hydroxy Propyl Methyl 0.1 g Cellulose 7 Benzalkonium Chloride 20 mg 8Ethylene Diamine Tetra 100 mg Acetic Acid (disodium salt) 9 Sodiumtetraborate (0.1 M) 3.81 g 10 Boric acid (1 M) 6.8 g 11 NaCl 0.795 g 12Sterile water for Injection 100 ml

Example 5 A Typical Nasal Formulation of 0.06% Curcumin

TABLE 5 S. No Ingredients Concentration 1 Curcumin 60 mg 2 PolyethyleneGlycol 1 g 4 Tween 80 1 g 6 Hydroxy Propyl Methyl 0.1 g Cellulose 7Benzalkonium Chloride 20 mg 8 Ethylene Diamine Tetra 100 mg Acetic Acid(disodium salt) 9 Sodium tetraborate (0.1 M) 3.81 g 10 Boric acid (1 M)6.8 g 11 NaCl 0.795 g 12 Sterile water for Injection 100 ml

Example 6 Comparison of Intracellular Transport of NanoemulsifiedCurcumin with Plain Curcumin

Subject: Caco-2 cell incubated with 60 μg/ml concentration ofnanoemulsified and plain curcumin were used in the study.

Experimental method: The study was conducted to evaluate the uptake ofnanoemulsified curcumin intracellularly. Cells were grown on thetranswell inserts to 100% confluence. The cells were then incubated withnanoemulsified and plain curcumin with a concentration of 60 μg/ml for 5minutes, 10 minutes and 20 minutes. At a later stage the inserts werewashed with HBSS buffer and fixed with 3% paraformaldehyde. The insertwas then cut and mounted on a slide and covered with a cover slip. Theseslides were then studied under confocal microscope at 63×. Themethodology of the test is detailed in Table-6 and the results aresummarized in FIG. 1.

TABLE 6 Cells Caco-2 Conc. Of Curcumin 60 μg/ml Treatment groups2(NE-nanoemulsified; NNE-non nanoemulsified Incubation period 5 min., 10min. and 20 min.

Example 7 Comparison of the Uptake of Nanoemulsifed Curcumin Vs. PlainCurcumin into Intestinal Cells of Mice Using the Isolated IntestinalLoop Model

Confocal microscopy studies were performed on cryosectioned miceintestinal tissue samples to determine the intracellular uptake ofcurcumin by the intestinal epithelial cells using the isolatedintestinal loop model. Briefly the mice were anesthetized withxylazine/ketamine and cut open. Following this, the intestines wereexposed and the ileum was identified and a loop was tied at the top andbottom of the ileum using surgical sutures without detaching from themesenchymal system after flushing out the intestinal contents. The drugsolutions at a concentration of 300 ug/ml for the respective groups wereintroduced into the lumen using a syringe with a polyethylene tubeattached to the needle and incubated for 60 minutes. After 60 minutesthe tissues were excised and frozen in liquid nitrogen immediately. Thetissues were then subjected to cryosectioning and mounted on a slide andcovered using a cover slip after which they were studied under theconfocal microscope at 63×. The results are summarized in FIG. 2.

No. of groups:—2 (Nanoemulsified (NE); Plain Curcumin (NNE))No. of animals/group:—2

Example 8 Particle Size Study Using Malvern Particle Size Analyzer

The particle size is analyzed by using Malvern particle size analyzer.The particle size (powder, suspensions and emulsions) is measured bydiffraction and diffusion of laser beam. For the purpose of laserdiffraction measurement, the particles are exposed to a laser beam. Theparticles scatter light at an angle that is inversely proportional totheir size. Photosensitive detectors are used to measure the angularintensity. A map of angle versus scattering intensity gives the particlesize value. The droplet size of the nanoemulsions was determined byMalvern particle size analyzer particle analyzer and was found to be10.55 nm. The results of particle size analysis by Malvern particle sizeanalyzer are summarized in FIG. 3.

TABLE 7 Peaks Size of the particles PDI Peak-1 10.55 0.2387

Example 9 Characterization of Nanoemulsion by TEM

The morphology and structure of the nanoemulsion were studied usingtransmission electron microscopy (TEM). A combination of bright-fieldimaging at increasing magnification and of diffraction modes was used toreveal the form and size of the nanoemulsion. To perform the TEMobservations, the nanoemulsion formulation was diluted with water(1/100). A drop of the diluted nanoemulsion was directly deposited onthe holey film grid and observed after drying. The image result ofnanoemulsion clearly showed that the nanoparticles are spherical inshape and size varied from 10-20 nm. The TEM image of the nanoemulsionis shown in FIG. 4

Example 10 Characterization of Nanoemulsion by SEM

SEM studies on the nanoemulsion showed that the particles were sphericalin shape and size was in nanometer range (FIG. 5). The particle size wasin the range of 10-20 nm.

Example 11 FRAP Assay (Total Antioxidant Activity) for Curcumin

The FRAP assay (TPTZ assay) developed by Benzie and Strain [R] wasemployed to measure the total antioxidant activity of the Curcumin incomparison to Vitamin C and Gallic acid. The assay mixture contained 2.5mL 300 mM acetate buffer pH 3.6, 0.25 mL 10 mM TPTZ solution in 40 mMHCl, 0.25 mL 20 mM FeCl3 and Curcumin in 0.1 mL water or methanol. 30minutes after incubation the absorbance was measured at 593 nm usingCary-50, UV-Vis spectrophotometer. Standard graphs were constructedusing known concentrations of ferrous salt in water/methanol to replaceFeCl₃. All tests were run in triplicate and mean values were used tocalculate EC1 values. EC1 is defined as concentration of antioxidanthaving a ferric reducing ability equivalent to that of 1 mM ferroussalt.

Result: The IC50 value in mcg/ml was found to be 6.92 for naturalcurcumin (FIG. 6).

Example 12 Anti-Allergic Study

The pre-clinical model used for the ocular allergy study is based onsensitizing the animals against the allergen egg albumin followed bychallenging the conjunctiva by egg albumin to produce ocular allergy.Twenty four animals (SD rats) in the age group of 10 to 14 weeks wereused for this study, comprising of four groups with 6 animals in eachgroup. Group 1 serves as a naïve control (neither induced nor treated),group 2 serves as the egg albumin induced group, group 3 serves as thecurcumin ophthalmic drops treated group and group 4 animals are treatedonly with the vehicle used for ophthalmic solution preparation. All theanimals in the group 2, group 3 and group 4 are sensitized with 1 mlintraperitoneal injection of suspension containing 100 μg egg albuminand 20 mg alum for 14 days. On 15^(th) day 10 μl of 1M DL-Dithiothreitol(DTT) in Phosphate buffered saline (pH—7.4) was applied to theconjunctiva and 10 min later the conjunctiva was topically challengedwith 10 μl egg albumin (100 mg/ml) prepared in phosphate-buffered salineto produce ocular allergy. Drug efficacy was tested by installing theCurcumin based ophthalmic solution to the eye of rats in group 3 bygently opening the eyelids of the rats 10 minutes before the DTT andallergen challenge. The animals in group 4 were treated with the similarmanner with the vehicle. The hyperemia and edema of the conjunctiva wasthen measured on a 0-4 point conjunctival scoring system at 0 min., 20min., 45 min., 90 min. and at the end of 4^(th) hour and theeffectiveness of the drug was shown by the reduction in conjunctivalredness and conjunctival edema when compared to baseline.

Example 13 Inhibition of β-Hexosaminidase by Nanoemulsified Curcumin

In a present study, the comparative efficacies on inhibition ofβ-Hexosaminidase release by unformulated and formulated compositions ofcurcumin (nanoemulsified) in Phorbol ester (PMA) induced model of U937human monocyte was assessed. Briefly, an equal number (50,000 cells) ofU937 human monocytes was plated in each well of a 96-well cell cultureplate. The cells were treated with different concentrations ofunformulated and formulated compositions of curcumin in presence orabsence of either 20 nM PMA. The cell culture supernatants collectedfrom either untreated control or treated cultures were clarified at10,000 g for 5 min. at 4° C.; and assessed for released β-hexosaminidase(6).

Measurement of Hexosaminidase

Twenty microliter aliquots of cell culture supernatant were incubatedwith 20 μl of 1 mM p-nitrophenyl-N-acetyl-β-D-glucosaminide in 0.1 Msodium citrate buffer (pH 4.5) at 37° C. for 1 h. At the end of theincubation, 250 μl of a 0.1 M Na₂CO₃, 0.1 M NaHCO₃ buffer (pH 10.0) wereadded. Absorbance was measured at 405 nm. Each treatment was done inquadruplicate wells. The mean OD obtained from the control cultures wasconsidered as 100% release of hexosaminidase.

The comparative efficacies in inhibiting β-hexosaminidase release bycurcumin and its respective nanoemulsified formulations in PMA inducedhuman monocytes are depicted in FIG. 7.

Example 15 Inhibition of Histamine Release by Nanoemulsified Curcumin

An equal number (50,000 cells) of U937 human monocytes were plated ineach well of 96-well cell culture plate. The cells were treated withdifferent concentrations of non-formulated and formulated curcumin(nanoemulsified) compositions in presence or absence of 20 nM PMA for 1h. The cell culture supernatants collected from either untreated controlor treated cultures were clarified at 10,000 g for 5 min at 4° C.; andassessed for released histamine by a commercially available EIA kit(SPI-Bio, France). The concentrations of the released histamine in theculture supernatants from PMA induced human monocytes treated withcurcumin and its nanoemulsified formulations are depicted in FIG. 8.

Method for Preparation of the Formulation: Preparation of Borate Buffer:

-   -   1) 3.81 g of sodium tetraborate was weighed into a beaker and        dissolved in 100 ml of water.    -   2) 6.8 g of boric acid was weighed into a beaker and dissolved        in 100 ml of water.    -   3) pH of sodium tetraborate solution was checked and found to be        in the range of 9. This was adjusted to a pH of 7.2 by the        addition of boric acid.    -   4) The buffer thus prepared was used to adjust pH of the        formulation.

Solubilization of Curcumin:

-   -   1) 60 mg curcumin was weighed into a 10 ml beaker    -   2) To this 1 g (765 ul) Tween80® and 1 g PEG was added and        stirred well using a glass rod.    -   3) Following this the tube was sonicated for 30 min. or until        the curcumin was completely solubulized.        -   A deep red color solution was formed.

Preparation of Ophthalmic Formulation:

-   -   1) 100 ml water was placed into a beaker on a magnetic stirrer.    -   2) HPMC was added and stirred till all the HPMC dissolved.    -   3) The curcumin+Tween80® solution was added drop by drop into        this and stirred for 15 mins.    -   4) To this BAC, EDTA and NaCl was added and stirred until all        the contents dissolve completely and a yellow color clear        solution was obtained.    -   5) pH of the solution was checked and found to be in the range        of 5.3-5.4. It was adjusted with the borate buffer to a pH of        6.5.

It will be evident to those skilled in the art that the invention is notlimited to the details of the foregoing disclosure and its illustrativeexamples, and that the present invention may be embodied in otherspecific forms without departing from the essential attributes thereof.It is therefore desired that the present embodiments and examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

We claim:
 1. A pharmaceutical composition for topical treatment of anasal or ocular condition, comprising: a nanoemulsified curcumincomponent, said curcumin component having a mean particle size ofbetween 5 nm and 30 nm, wherein said curcumin component is selected fromthe group consisting of a natural curcuminoid, a synthetic curcuminoid,a metabolite of a natural or synthetic curcuminoid, and a mixturethereof; an aqueous carrier, and a pharmaceutically acceptableexcipient.
 2. The composition according to claim 1, wherein the curcumincomponent comprises a compound selected from the group consisting ofcurcumin, bisdemethoxycurcumin, demethoxycurcumin, a demethylatedcurcuminoid, and a mixture thereof.
 3. The composition according toclaim 2, wherein the demethylated curcuminoid is bis-O-demethylcurcumin.
 4. The composition according to claim 1, wherein the curcumincomponent has a mean particle size between about 10 nm and about 20 nm.5. The composition according to claim 1, wherein the pharmaceuticalcomposition comprises the nano emulsified curcumin component in anamount ranging from about 0.01% to about 5% w/v.
 6. The compositionaccording to claim 5, wherein the pharmaceutical composition comprisesthe nano emulsified curcumin component in an amount ranging from about0.05% to about 0.15% w/v.
 7. The composition according to claim 1,wherein the curcumin component comprises at least one compound derivedfrom a species selected from the group consisting of Curcuma longa,Curcuma aromatica, Curcuma zedoaria, and combinations thereof.
 8. Thecomposition as claimed in claim 1, wherein the pharmaceuticallyacceptable excipient is selected from the group consisting of asurfactant, a co-solvent, and a mixture thereof.
 9. The compositionaccording to claim 8, wherein the surfactant is selected from the groupconsisting of anionic surfactants, cationic surfactants, non-ionicsurfactants, and mixtures thereof.
 10. The composition according toclaim 8, wherein the surfactant is selected from the group consisting ofpolysorbate 80, polysorbate 20, polyethylene glycol esters, polyethyleneglycols, glycerol ethers, and mixtures thereof.
 11. The compositionaccording to claim 8, wherein the co-solvent is selected from the groupconsisting of monohydric alcohols, polyhydric alcohols, polyethyleneglycols, polypropylene glycols, and mixtures thereof.
 12. Thecomposition according to claim 1, wherein the composition furthercomprises at least one additive selected from the group consisting of awater soluble polymer, a chelating agent, a stabilizing agent, anisotonizing agent, a buffer substance, a preservative, a thickener, anelectrolyte and mixtures thereof.
 13. The composition according to claim12, wherein the water soluble polymer is selected from the groupconsisting of methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose,sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,polyethylene glycol, poly(methyl methacrylate), polycarbophil, gelatin,alginate, poly(acrylic acid), polyethylene oxide, chitosan, derivativesthereof, and mixtures thereof.
 14. The composition according to claim12, wherein the chelating agent is a disodium salt of EDTA.
 15. Thecomposition according to claim 12, wherein the stabilizing agent isselected from the group consisting of sodium hydrogen sulfite, glycerin,sodium citrate, butyl hydroxyanisole, edetic acid and pharmaceuticallyacceptable salts thereof, tocopherol, derivatives thereof, and mixturesthereof, alone or in combination with sodium edetate.
 16. Thecomposition according to claim 12, wherein the isotonizing agent isselected from the group consisting of sodium chloride, potassiumchloride, D-mannitol, glucose, glycerin, xylitol, propylene glycol, andmixtures thereof.
 17. The composition according to claim 12, wherein thethickening agent is selected from the group consisting ofmethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose,polyvinyl pyrrolidone, polyvinyl alcohol, sodium chondroitin sulfate,sodium hyaluronate, chitosan, and mixtures thereof.
 18. The compositionaccording to claim 12, wherein the preservative is selected from thegroup consisting of sodium bisulfite, sodium bisulfate, sodiumthiosulfate, benzalkonium chloride, chlorobutanol, thimerosal,phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinylalcohol and phenylethyl alcohol, and mixtures thereof.
 19. Thecomposition according to claim 12, wherein the buffering agent comprisesa base selected from the group consisting of sodium carbonate, sodiumtetraborate, sodium phosphate, sodium acetate, sodium bicarbonate, andmixtures thereof.
 20. The composition according to claim 12, wherein theelectrolyte is sodium chloride or potassium chloride.
 21. Apharmaceutical composition for treating allergic conditions comprising:a carrier comprising a liquid medium; a nanoemulsified curcumincomponent having a mean particle size of between 5 nm and 30 nm withinsaid liquid medium, said curcumin component being selected from thegroup consisting of a natural curcuminoid, a synthetic curcuminoid, ametabolite of a natural or synthetic curcuminoid, and a mixture thereof;and a pharmaceutically acceptable excipient, said excipient beingeffective in increasing the bioavailability of the curcumin component.